Effects of oxo and dihydro metabolites of 12-hydroxy-5,8,10,14-eicosatetraenoic acid on chemotaxis and cytosolic calcium levels in human neutrophils.
One of the pathways of metabolism of leukotriene B4 (LTB4) and 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) in leukocytes is oxidation of the 12-hydroxyl group, followed by reduction of the 10,11-double bond. In the case of 12R-HETE and 12S-HETE, this results in the formation of 12-oxo-ETE, 10,11-dihydro-12-oxo-ETE, and the 12R and 12S isomers of 10,11-dihydro-12-HETE (i.e., 12R-HETrE and 12S-HETrE). We investigated the effects of metabolites of 12-HETE formed by this pathway on cytosolic calcium levels and chemotaxis in human neutrophils. Of the above series of metabolites, 12S-HETrE (which has the same absolute stereochemistry at C-12 as 12R-HETE) was the most potent in stimulating both cytosolic calcium levels and chemotaxis. It was slightly less potent than 12R-HETE, consistent with the concept that reduction of the 10,11-double bond results in a loss of biological activity on neutrophils. The effect of 12S-HETrE on calcium levels was blocked by preincubation of these cells with LTB4, suggesting that it acted by stimulating the LTB4 receptor. 12R-HETrE was about 20 times less potent than its 12S isomer in stimulating cytosolic calcium in neutrophils and was also less active as a chemotactic agent. Oxidation of the 12-hydroxyl group to an oxo group resulted in a further loss of biological activity. 12-Oxo-ETE, 8-trans-12-oxo-ETE, and 12-oxo-ETrE had only modest effects on cytosolic calcium levels at concentrations as high as 10 microM and did not display detectable chemotactic activity. However, 12-oxo-ETE and its 8-trans isomer inhibited calcium responses to LTB4 by about 40%. It is concluded that reduction of the 10,11-double bond of 12-HETE results in a slight loss of biological activity on neutrophils, whereas oxidation of the 12-hydroxyl group results in a considerably greater loss of activity.[1]References
- Effects of oxo and dihydro metabolites of 12-hydroxy-5,8,10,14-eicosatetraenoic acid on chemotaxis and cytosolic calcium levels in human neutrophils. Powell, W.S., Hashefi, M., Falck, J.R., Chauhan, K., Rokach, J., Wang, S.S., Mills, E., MacLeod, R.J. J. Leukoc. Biol. (1995) [Pubmed]
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